The overall goal of this research is to elucidate the role of blood rheology as a determinant of microvascular function in health and disease. To this end, techniques of intravital microscopy will be applied to evaluate the extent to which red blood cell (RBC) deformability and aggregation, and white blood cell (WBC) deformability and adhesion to the endothelium, affect the resistance to blood flow in vessels ranging from the true capillaries, to the arterioles and venules which serve them. Quantitative indices of microvascular function will be derived from direct in situ measurements of hemodynamic variables in exteriorized tissues such as the mesentery, omentum and cremaster muscle. Specific aims are to elucidate the relationship between blood flow and blood coli mechanical properties within individual microvessels, at branch points throughout the microvascular network and regionally throughout the succession of major microvascular divisions. A major emphasis of the research will be to elucidate microvascular function in the low flow state by either mechanical obstruction of the arterial inflow, hemorrhagic hypotension or pharmacological intervention. Specific studies on RBCs will delineate the role of red cell aggregation in the margination of WBCs, regional resistance to blood flow and recovery from prolonged ischemic episodes. Studies on RBC deformability will seek to elucidate the effect of its decrease on the process of capillary recruitment during tissue hypoxia, its effect on regional resistance to flow and on the resistance to flow in single unbranched microvessels. Studies on RBC concentration will aim to elucidate the relationship between average tissue hematocrit, determined by the dynamics of red cell flux through the microvasculature, and the tube hematocrit, obtained by direct measurements in individual microvessels. The role of WBC deformability will be examined as a determinant of WBC adhesion to the endothelium and resistance to flow. Techniques of optical sectioning microscopy will be applied to elucidate the role that irregularities in the microvessel lumen play in affecting the resistance to blood flow. It is anticipated that the results of these studies will provide insight into the role of mechanical and biochemical properties of blood cells in affecting microvascular function and aid development of therapeutic strategies to treat a variety of pathologies such as anemia, polycythemia, the low flow state, shock, inflammation and blood cell disorders, to name a few.